Alzheimer's Disease (AD) is a devastatingly progressive, fatal neurodegenerative disease. With approximately 30 million patients affected worldwide, it is the most common form of dementia and is predicted to grow exponentially. The pathology of AD is driven by Amyloid Precursor Protein (APP) and it's proteolytic processed products, primarily the A?42 peptide, leading to amyloid plaques, Tau-containing neurofibrillary tangles and neuron death. Although there are four FDA approved drugs to treat AD, unfortunately none of these address the underlying genetic and molecular basis of AD. At best, they provide temporary, symptomatic improvement. Consequently, there remains a great medical need to develop AD therapies that selectively target the APP driven pathogenesis to prevent cognitive dysfunction and neuron death. In contrast to the current bleak picture for treating AD, the field of RNA therapeutics, including Antisense Oligonucleotides (ASOs) and siRNA RNAi responses, has come of age in the clinics. Spinraza, a splice altering ASO for treating SMA in the CNS, was approved in 2016. Onpattro, the first siRNA therapeutic, was approved in 2018 for treating hereditary ATTR amyloidosis. There are currently >30 RNA therapeutics in the clinics. RNAi therapeutics have exquisite target selectivity for all mRNAs, including APP, plus a single dose can achieve 3 to 9 month duration of response in patients. CNS-wide knockdown of APP by siRNAs would result in unacceptable gross alteration of brain functioning and cognitive decline. Therefore, our overarching goal is to develop precision genetic medicine APP Antibody-RNAi Conjugates (ARCs) that specifically knockdown APP in selectively vulnerable basal frontal cholinergic neurons (BFCNs) in the CNS of AD mouse models. A recent advance in siRNA chemistry has shown a breakthrough for delivery throughout the CNS, including neurons. This opens the door for our proposal to develop next- generation APP RNAi triggers to selectively knockdown APP only in BFCN neurons in AD mouse models